Although the field of anesthesiology has played a leadership role in promoting patient safety, there is still no standard monitor for the target orga of general anesthesia: the brain. The lack of reliable neurophysiologic monitoring can result in patient complications because of insufficient anesthesia (e.g., awareness and post- traumatic stress disorder) as well as excessive anesthesia (e.g., delayed emergence, delirium, neurotoxicity). A number of commercially-available brain monitors are currently used in the operating room, but such devices have shown limited utility and are often based on proprietary or empirical algorithms. Recent advances in neurobiology herald the possibility of a more sophisticated era of brain monitoring and improved patient safety. What is urgently needed is the identification of measurable neurophysiologic features of general anesthesia that are informed by the neurobiology of consciousness and that can be explained by neurochemical mechanisms. We have recently performed both human and animal studies that identify preferential inhibition of frontal-to-parietal feedback connectivity in the brain as a candidate neurophysiologic correlate of general anesthesia. However, it is still unclear how cortical feedback inhibition during anesthesia is best measured, how sensitive it is to changing states of consciousness, and what the underlying mechanisms are. Our long-term goal is to develop a neurophysiologic monitor for general anesthesia that improves patient safety. The objective of the proposed studies is to demonstrate that preferential inhibition of frontoparietal feedback connectivity is a reliable measure of general anesthesia in humans as well as to elucidate its neurochemical mechanisms in an animal model. Our central hypothesis is that frontoparietal feedback inhibition is a common network-level mechanism of general anesthesia that is regulated by acetylcholine activity in the prefrontal cortex. The rationale for the proposed research is that understanding anesthetic- induced changes in frontoparietal connectivity will significantly impact clinical practice by improved patient monitoring. Furthermore, a mechanistic understanding of the role of acetylcholine in network connectivity will advance the anesthetic care of patients at risk for dementia or delirium, both of which are thought to involve cholinergic neurotransmission. Finally, this fundamental work on feedback connectivity will help advance the understanding of pathologic states of unconsciousness, because selective feedback inhibition has recently been shown to be associated with vegetative states. PUBLIC HEALTH RELEVANCE: This project is relevant to public health because it seeks to understand how general anesthetics affect the brain and how this can best be measured. Gaining a more detailed knowledge of anesthesia and the brain will help improve patient care through better monitoring in the operating room and the development of safer anesthetic drugs.